Derivatives of 1 2 3 4-tetrahydrobenzothieno(2 3-c)pyridines

ABSTRACT

THE COMPOUNDS ARE DERIVATIVES OF 1,2,3,4 - TETRAHYDROBENZOTHIENO(2,3 - C)PYRIDINES AND 1,2,3,4 - TETRAHYDRO5H - BENZOTHIENO(2,3 - C)AZEPINES USEFUL AS TRANQUILIZING AND ANTIHYPERTENSIVE AGENTS. COMPOUNDS DISCLOSED ARE 2 - B - DIETHYLAMINOPROPYL - 1 - PHENYL - 1,2,3,4 - TETRAHYDROBENZOTHIENO(2,3 - C)PYRIDINE AND 1 - (P - CHLOROPHENYL) - 1,2,3,4 - TETRAHYDROBENZOTHIENO(2,3-C)PYRIDINE.

United States Patent U.s. Cl. 260'2 94.8 B 7 Claims ABSTRACT on THEDISCLOSURE The compounds are derivatives of 1,2,3,4tetrahydrob'enzothieno[2,3 C]pyridines and 1,2,3,4 tetrahydro- Hbenzothieno[2,3 C]azepines useful as tranquilizing and antihypertensiveagents. Compounds disclosed are 2 3 diethylaminopropyl 1 phenyl l,2,3,4tetrahydrobenzothieno[2,3' C]pyridine and 1 (p chlorophenyl) 1,2,3,4tetrahydrobenzothieno[2,3=C]pyridine.

RELATED CASES The present application in a continuation-in-part of mycopending application Ser. No. 705,909 filed Feb. 16, 1968, now US. Pat.No. 3,520,895 which is in turn a continuation-in-part of my earlierapplication Ser. No. 621,475 filed Mar. 8, 1967, now abandoned.

DETAILED DESCRIPTION The compounds of the present invention have thefollowing formula wherein A and A are selected from hydrogen, hydroxy,nitro, lower alkyl groups of 1 to 4 carbon atoms such as methyl, ethylor isopropyl, lower alkoxy groups such as methoxy, ethoxy and propoxy,halo such as bromo, chloro and fluoro and trifluoromethyl, m is 1 or 2,R is a group selected from hydrogen, a lower alkyl of l to 4 carbonatoms, an aralkyl of 7 to 11 carbon atoms, such as benzyl, phenethyl andphenylisopropyl and including halo and lower alkoxy substitutedphenyl-lower alkyls such as o-chlorobenzyl and p-methoxybenzyl, (CH OHin which n is 2 to 6, and BAm in which B is an alkylene of 2 to 6 carbonatoms and Am is selected from in which R and 12 maybe the same ordifferent groups selected from hydrogen, lower alkyl of 1 to 4 carbonatoms, lower alkyl-tertiaryamino such as diethylamino- 3,651,068Patented Mar. 21, 1972 ice ethyl, hydroxy-lower alkyl such ashydroxyethyl, a lower alkenyl of 3 to 6 carbon atoms such as allyl andhexenyl, phenyl, nuclear substituted phenyl, particularly a halophenylsuch as o-chlorophenyl and an alkoxyphenyl such as p-methoxyphenyl,cycloalkyl groups, particularly those containing 3 to 7 carbon atoms andincluding cyclohexyl and cyclopentyl, cycloalkyl-lower alkyl groups,particularly those in which the cycloalkyl contains 3 to 7 carbon atomssuch as cyclohexyl-methyl and cyclopentylethyl,

( b) Groups in which represents an amino group such as morpholino,pyrrolidino, piperidino, N-lower alkyl piperazino groups such asN-methyl-piperazino, N-(phenyl-lower alkyl)- piperazino groups such asN-benzylpiperazino and 4- (alpha-methylphenethyl)-piperazino and N(hydroxylower alkyl)-piperazino groups such as4-(beta-hydroxyethyl)-piperazino and (0) Am is a cyclic amine groupbonded through a nuclear carbon to B, including such groups as N-loweralkyl-2,3 or 4-piperidyls such as N-methyl-3-piperidyl, N-ethyl 4piperidyl, N-ethyl-Z-piperidyl and N-isopropyl 3 piperidyl, N-(di-loweralkyl amino-lower alkyl)- 2,3 or, 4-piperidyls such asN-(beta-dimethylaminopropyl) piperidyl, N (betadiethylaminoethyD-3-piperidy and N (beta dimethylaminopropyl) 2piperidyl, N phenyl-lower alkyl-3 or 4-piperidyls such as N- benzyl 3piperidyl, N-phenylethyl 4 piperidyl and N-phenylpropyl 3 piperidyl,2-piperidyl, 3-piperidy1 and 4-piperidyl, 2-pyrrolidyl, 3-pyrrolidyl,N-lower alkyl- 2 or 3-pyrrolidyls such as N-methyl 2 pyrrolidyl, N-ethyl 3 pyrrolidyl, N-propyl 4 pyrrolidyl, and N- phenyl-lower alkyl-2or 3-pyrrolidyls such as N benzyl- 2 pyrrolidyl and N-phenyl-ethyl 3pyrrolidyl, X is hydrogen or lower alkyl and X is hydrogen, a loweralkyl of 1 to 4 carbon atoms, phenyl including a nuclear substitutedphenyl, particularly a halophenyl such as ochlorophenyl, or analkoxyphenyl such as p-methoxyphenyl, aralkyl of 7 to 11 carbon atomssuch as benzyl, phenethyl and phenylisopropyl and including nuclearsubstituted aralkyls, particularly halo and lower alkoxy substitutedphenyl-lower alkyls, such as o-chlorobenzyl and dimethoxybenzyl, aheterocyclic such as pyridyl, piperidyl, furyl, thienyl, pyrryl andpyrrolidyl or BAm.

The basic starting materials employed in the preparation of thecompounds of the present invention are fl-(3- thianaphthenyl)alkylaminesof the formula These amines may be prepared from the corresponding cyanocompounds as described in the literature. [Herz I.A.C.S. 72, p. 4999(1950)] The starting materials may also be prepared by treating thecorresponding acid with thionyl chloride followed by treatment withsodium azide and acid hydrolysis. The process may be illustrated asfollows:

OOH

Cl (C H2) in] (C Hz) m Representative of the amines which may beemployed are the following: p-(3-thianaphthenyl)ethylamine,p-(5-chloro-3-thianaphthenyl)ethylamine,p-(5-hydroxy-3-thianaphthenyl)ethylamine,fl-(6-trifiuoromethyl-3-thianaphthenyl)ethylamine,fl-(7-methoxy-3-thianaphthenyl)ethylamine,p-(4-bromo-3-thianaphthenyl)ethylamine, and'y-(3-thianaphthenyl)propylamine.

The compounds of the present invention which are represented by theformula (CHz)m NH s/\/( Ar wherein X is hydrogen may be prepared bytreating a p-(3-thianaphthenyl)ethylamine with a suitable aldehyde in aconcentrated liquid organic acid such as glacial acetic acid.

The above described process may be diagrammed as follows:

xiii-H wherein A and A are as described and do not interfere with apartake in the reaction Representative of the aldehydes whichmay be-employed in the described process are the following:

Pyridine-4-carboxaldehyde, Pyridine-Z-carboxaldehyde, Benzaldehyde,p-Methoxybenzaldehyde, Dimethylaminobenzaldehyde, Z-furaldehyde, I2-pyrro1icarboxaldehyde, 3-pyrrolecarboxaldehyde,2-thiophenecarboxaldehyde, and 3-thiophenecarboxaldehyde.

Representative of the compounds which may be pre-,;

pared by the described process are the following:

1-(p-chlorophenyl)-1,2,3,4-tetrahydrobenzothieno [2,3-C]-PY idine,1-(4-pyridyl)-1,2,3,4-tetrahydrobenzothieno[239C] pyridine,

l phenyl-1,2,3,4-tetrahydrobenzothieno[2,3-C] pyridinel-phenyl-1,2,3,4-tetrahydro-5H-benzothieno[2,3-C] azepine,

l-ethyl-1,2,3,4-tetrahydro-5H-benzothieno[2,3-C] i azepine,1-(p-chlorophenyl)-1,2, 3,4rtetrahydro-5H-benzothieno [2,3-C]azepine,1-(p-trifiuoromethylphenyl)-1,2,3,4-tetrahydro-5Hbenzothieno[2,3-C]azepine,1-(2'-pyridyl)-1,2,3,4-tetrahydro-5H-benzothieno- [2,3-C1azepine,

1-( p-methoxyphenyl)-l,2,3,4-tetrahydrobenzothieno- I1-(3'-furyl)-6-hydroxy-1,2,3,4-tetrahydrobenzothieno v [2,3-C1pyridine.

The compounds which are represented by the formula in which X is otherthan hydrogen may be prepared by a variety of methods. The compounds in-which =X is methyl may be prepared by treating an appropriate amine vwith a methyl ketone in the presence of a p-toluenesulfonic acid andtoluene followed by treatment with an acid such as hydrogen chlorideinan inert solvent such as ether. The described process may be illustratedas follows:

p-toluenesulfonic acid toluene i s r A1 Xx X2 H Xi wherein X is methyland A and A are as described and represent groups that do not partake inor interfere with the reaction. I

Representative of the ketones which may be employed in the describedprocess are the following:

Acetone, Methyl ethyl ketone, 3-pentanone, 2-pentanone, andAcetophenonei Representative of the compounds which may be prepared bythe described process are the following:

1,1-dimethyl-l,2,3,4-tetrahydrobenzothieno[2,3-C]

py v l-ethyl-l-methyl-1,2,3,4-tetrahydrobenzothieno[2,3-C]

pyridine, l-methyl-l-phenyl-1,2,3,4-tetrahydrobenzothieno[2,3-C]

pyridine, l-methyl-1-phenyl-1,2,3,4-tetrahydro-Sfi benzothieno-[2,3-C1azepine, and 1, l-dimethyl- 1 ,2,3,4-tetrahydro-5H-benzothieno[2,3 -C] azepine.

The compounds in'which X is hydrogen and X is alkyl or aralkyl may alsobe prepared by first treating the corresponding amine with aconventional acylating agent such as an acyl halide, anhydride or ester,in a suitable solvent such as benzene, toluene or xylene, preferably atreflux temperature to form the corresponding amide. The resulting amideis then treated with phosphorus pentoxide and phosphorus oxychloride ina suitable anhydrous medium such as xylene or toluene, to form the ringunsaturated 3,4-dihydrothianaphthieno[2,3-C]pyridine derivative whichupon treatment with lithium aluminum hydride yields the desired ringsaturated compound.

The above described process may be illustrated as fol- V We, NH:

r0013 f P2 5 wherein A and A are as described and represent groups thatdo not interfere with or partake in the reactions.

Representative of the acylating agents which may be employed are thefollowing:

Representative of some of the amides prepared by the process are thefollowing:

N-acetyl-B- 3 -thianaphthenyl) ethylamine,

N-acetyl-y- 3-thianaphthenyl propylamine,

N-3-nitropropionyl-13-(3'-thianaphthenyl) ethylamine,

N-3-nitropro pi011yl-'y-( 3 '-thianaphthenyl propylamine,

N- 3 ,4-dimethoxyphenylacetyl) 19- (S-thianaphthenyl) ethylamine,

N- 3,4-dimethoxyphenylacetyl) -'y- (3-thianaphthenyl) propylamine,

N-acryloyl-B- 3 -thianaphthenyl) ethylamine,

N-acryloyl-y- (3 -thianaphthenyl propylamine,

N-propionyLp- (3 -thianaphthenyl ethylamine,

N-propionyl-y- 3-thianaphthenyl) propylamine,

N- (p-methoxyphenylacetyl) 8- (3-thianaphthenyl) ethylamine,

N- p-methoxyphenylacetyl) --y- 3-thianaphthenyl propylamine,

N-iso-butyryl-B- 3-thianaphthenyl ethylamine,

N-iso-butyryl-y- 3 -thianaphthenyl) propylamine,

N-butyryl-,3 (3 -thianaphthenyl) ethylamine,

N-butyryl-v- 3 -thianaphthenyl) propylamine,

N- fl- (N'-methylpiperazino ropionyl] -[3- 3-thianaphthenyl) ethylamine,

N- B'- (N'-methylpiperazino) propionyl] w- (3 -thian aphthenyl)propylamine,

N-methyl-N- 8- (diethylamino) propionyl] -fi- S-chloro-B-thianaphthenyl)ethylamine,

N-methyl-N- fi- (diethylamino propionyl] -'y-(5-ChlO1'O-3thianaphthenyl) propylamine,

N-B-morpholinopropionyl-fi'- (6-trifluoromethyl-3-thianaphthenyl)ethylamine,

N-,8- 3- (N-ethyl )pyrrolidyl] -e'- (7'-methoxy-3 '-thianaphthenyl)ethylamine,

N-dimethylaminoacetyl-B- (5 -fluoro-3 -thianaphthenyl) ethylamine, I I

N-dimethylamino acetyl-v- (5-fiuoro-3 -thianaphthenyl) propylamine,

N-'ydiethylamine )butyryl-fi'- 5-hydroxy-3 -thianaphthenyl) ethylamine,

N-ydiethylamino) butyryl-'y- (5-hydroxy-3- I thianaphthenyl)propylamine,

N-B- (N-hydroxyethylpiperazino propionyl-B'- (5-.

trifluoromethyl-3-thian aphthenyl) ethylamine, and

N-B- N'-hydroxyethylpiperazino) ropionyl-y- 5'-trifluoromethyl-3-thianaphthenyl pro pylamine.

1,2,3,4-tetrahydrobenzothieno[2,3-C]pyridines and 1,2,3-'

4-tetrahydro-5H-benzothieno[2,3-C1azepines which may be prepared are thefollowing:

l-iso-propyl-3,4dihydrobenzothieno [2,3-C] pyridine,

1-iso-propyl-3 ,4-dihydro-5H-benzothieno [2,3-C] azepine,

1- (p-diethylaminoethyl -6-hydroxy-3,4-dihydrobenzothieno[2,3-C]pyridine,

1- fl-diethylaminoethyl) -6-hydroxy-3 ,4-dihydro-5H- benzothieno [2,3-C]azepine,

1-methyl-3 ,4-dihydrobenzothieno [2,3-C] pyridine,

1-methyl-3,4-dihydro-5H-benz0thieno [2,3 -C] azepine,

1- (3 ',4-dimethoxyphenyl) -3 ,4-dihydrobenzothieno [2,3-C] pyridine,

1- (3 ,4'-dimethoxyphenyl -3,4-dihydro-5H-benzothieno [2,3-C] azepine,

-6-chlorol-ethyl-3,4-dihydrobenzothieno [2,3 -C] pyridine,

6-chloro- 1-ethyl-3 ,4-dihydro-5H-benzothieno [2,3-C]

azepine,

1- [4'- (N-methylpiperidyl) ]-7-trifluoromethyl-3 ,4-dihydrobenzothieno[2,3 -C] Pyridine,

1- [4'- N-methylpiperidyl) ]-7-trifluoromethyl-3,4-dihydro-S-H-benzothieno [2,3-C] azepine,

1- [B- (N-hydroxyethylpiperazino ethyl] -7-methoxy-3,4-

dihydrobenzothieno [2,3-C] pyridine,

6-hydroxy- 1- (N-methylpiperazinoethyl) -3 ,4-dihydrobenzothieno [2,3-]pyridine,

l-iso-propyll,2,3,4-tetrahydrobenzothieno [2,3-C]

l-iso-propyl-1,2,3 ,4-tetrahydro-H-benzothieno 2,3-C]

azepine,

l-ethyl-l ,2,4,4-tetrahydrobenzothieno [2,3 -C] pyridine,

i 1- [p- (N-hydroxyethylpiperazino ethyl]-7-methoxy-1,2,3,4-tetrahydrobenzothieno[2,3-C1pyridine, and6-hydroxy-l:(N-methylpiperazinoethyl)-1,2,3,4-tetrahydrobenzothieno[2,3-C]pyridine.

The compounds of the present invention in which R, X and X, are hydrogenmay be prepared by several methods. For example, they may be prepared-bytreating a corresponding amine with paraformaldehyde in an acetatebuffer such as sodium acetate and acetic acid or by reduc? tion of thecorresponding lactam. The two processes may be diagrammed as follows: i

A A WM V H2)m 2)m I l I 1H3 /l 1H A1 S Ar s \cmo fiAH metal hydride suchas lithium aluminum hydride. The

compounds in which R is methyl are most conveniently prepared bytreating the unsubstituted compound with formaldehyde and formic acid.

The described processes may be illustrated as follows:

( 2)m 0 (CH2)!!! 1 H HO 7 NH HCOOH N-CH; s Y s K A1 1 X2 X1 X1 laid;

( H2)m-| E X1 X: 1 X2 wherein RX is an alkylating agent such asan al-kylhalide or a reactive ester and O R-Hl-X is an acyl halide.

Representative of the compounds which may be prepared by the describedprocesses are the following:

1-ethyl-2-methyl-6-methoxy 1,2,3,4-tetrahydrobenzothieno[2,3-C1pyridine,1-ethyl-2-methyl-6-methoxy-l,2,3,4-tetrahydro-5H-benzothieno[2,3-C]azepine,1-methyl-2-benzyl-7-chloro-l,2,3,4-tetrahydrobenzothieno[2,3-C1pyridine,1-methyl-2-benzyl-7-chloro-l,2,3,4-tetrahydro-5H-benzothieno[2,3-C1azepine, r1-p-dimethylaminoethyl-Z-ethyl-l,2,3,4-tetrahydrobenzothieno[2,3-C1pyridine, I 1-fl-d.imethylaminoethyl-2ethyl-l,2,3,4-tetrahydro-5H- H benzothieno[2,3-C] azepine,1,1,2-trimethyl-8-fluoro-1,2,3,4-tetrahydrobenzothieno- [2, 1py idthieno[2,3-C1azepine.

The compounds of the present invention which are represented by theformula in which R is B-Am are conveniently prepared by first treating acorresponding unsubstituted compound with an aminoacyl' halide to formthe corresponding acyl amine derivative and then treating it with achemical reducing agent such as LAH or other metal hydrides to form theamine derivative.

The described process may be illustrated as follows:

7 NH 3 A1 K X1 Xz (CH2)m 7 t N- BAm A 1 X1 X2 lLAH N-orn-B-Am s r X1 X:where X X A and A are as described and do not interfere with or partakein the reaction.

Representative of the aminoacylhalides which may be used in the abovedescribed process are the following:

3- (diethylamino)propionyl halide,

2- (dimethylamino)acetyl halide, 3-(N-benzyl-N-methylamino)propionylbromide, 2-(N,N-dibenzylamino) acetyl halide,3-(N-phenyl-N-methylamino)propionyl bromide,'y-'(N-methylpiperazino)butyryl chloride,

8- (N-methylpiperazino)propionyl chloride, fl-(morpho1ino)propionylchloride, p-[3-(N-methyl)pyrrolidyl]propionyl chloride, and-t(piperidyl)butyryl chloride.

Representative of the compounds which may be prepared in the describedmanner are the following:

1 0 1-ethyl-2-fi-diethylaminopropionyl-6 chloro-1,2,3,4-tetrahydro-5H-benzoth ieno 2,3-C] azepine, g ly-dimethylaminopropybZ-acetylJ-methoxy-1,2',3,4-,

tetrahydrobenzothieno [2, 3-C] pyridine, i1-'y-dimethylaminopropyl-2-acetyl-7-methoxy-1,2,3,4-

tetrahydro-SH-benzothieno [2,3-C] azepine, t l-4'-pyridyl-2-fi-N-methylpiperazinopropionyl) -8-fluoro 1,2,3 ,4-tetrahydrobenzothieno[2,3-C]pyridine,Z-B-diethylaminopropyl-1-phenyl-1,2,3,4-tetrahydrobenzothieno [2,3-C]pyridine,2-,8-diethy1aminopropyl-1-pheny1-l,2,3,4-tetrahydro-5H-benzothieno [2,3-C] azepine, Z-B-diethylaminopropyll-methyl- 1,2,3,4-tetrahydrobenzothieno [2, 3-C] pyridine,Z-fl-diethylaminopropyl-l-methyl-1,2,3 ,4-tetrahydro-SH-benzothieno[2,3-C] azepine,Z-B-dimethylaminoethyl-1-pheny1-1,2,3,4-tetrahydrobenzothieno [2,3-C]pyridine, Z-fl-dimethylaminoethyl-1-phenyl-1,2,3,4tetrahydro-SH-benzothieno [2,3 -C] azepine,Z-B-dimethylaminoethyll-methyl- 1,2, 3 ,4-tetrahydrobenzothieno [2,3-C]pyridine, 2-fi-dimethylaminoethyl-1-methyl-1,2,3,4-tetrahydro-SH-benzothieno [2,3 -C] azepine,1-5-dimethylaminoethyl-2-ethyl-7-methoxy-1,2,3,4-tetrahydrobenozthieno[2,3 -C] pyridine, 1-ethyl-2-fi-N-methylpiperazinoethyl- 6- chloro-l,2,3 ,4-

tetrahydrobenzothieno [2,3 -C] pyridine, and 1- (4'-pyridyl )-2-B-diethylaminoethyl) -6-trifluoromethyl- 1,2, 3,4-tetrahydrobenzothieno[2, 23-0] pyridine.

The compounds in which R is a BAm may also be prepared by first treatingthe corresponding unsubstituted compound with an 0:,5 unsaturated acylhalide, such as acrylic halide, followed by treatment with an amine andlithium aluminum hydride.

The described process may be illustrated as follows:

( C H2) m--i J, CH CH i l-halo lH-Am lLAH I (Guam-l I N-CHz-CHz-CHz-Am 1s y cause of their commercial unavailability. 1 r rRepresentative-of-the compounds which, might beconvenientlypreparedbythe described method are the followingr fg 1-methyl;2-( n -methylpi peraz inopropionyl -1-phenyl- "1,2;3,4 teuahydro-5H-ben2othieno[2,3-C] pyridine,

1-methyl-2- iy-4Gmethylpiperazindpropy1) -1-ph'eny11,2,3,4-tetrahydrobenzothieno[2,3 C]pyridine,

1-methyl-2-(-y-4-methylpiperazinopropyl)-l-phenyl- 1,2,3,4-tetrahydro5H-benzothieno[2,3 azepine,

1-methyl-2-(ry-'-methylpipe'razinopropyll-l-methyll,2,3,4-tetrahydrobenzothieno[2,3'-C] pyridine,

1-methy1-2-('y-4-methylpiperazinopropyl) -1-methyl-1,2,3,4-tetrahydro-H-benzothieno [2,3-C] azepine,

2- B-4'-methylpiperazinopropionyl -1-phenyl-1,2,3 ,4-

tetrahydrobenzothieno[2,3-C]pyridine,

2- (18-4'-methy1piperazinopropionyl) -1-phenyl- 1,2,3 ,4-

tetrahydro-SH-benzothieno [2,3-C] azepine,

2-('y-4'-methylpiperazinopropyl)-1-phenyl-1,2,3,4-

tetrahydrobenzothieno[2,3-C]pyridine,

2-('y-4'-methylpiperazinopropyl)-1-phenyl-l,2,3,4-

tetrahydro-SH-benzothieno [2,3-C] azepine,

2- 'y-4'-methylpiperazinopropyl) -1-methyl- 1,2,3 ,4-

tetrahydrobenzothieno[2,3-C1pyridine,

6-chloro-1-(,8-dimethylaminoethyl)-2-(fi-N'-hydroxyethylpiperazinopropionyl)-1,2,3,4-tetrahydrobenzol-ethyl-7-hydroxy-2-(p-diethylaminopropionyl)-1,2,3,4-

tetrahydrobenzothieno [2,3-C] pyridine,

1--(4'-pyridyl)-2-(,H'-N-methylpiperazinopropionyl)-1,2,3,

4-tetrahydrobenzothieno[2,3-C]pyridine, and

1- [4'- (N'-methy1piperidyl) ]-6-methoxy-2-propionyl- 1,2,

3 ,4-tetrahydrobenzothieno [2,3-C] pyridine.

A variety of compounds in which R is other than amino may also beprepared by use of conventional techniques. For example, the compoundsin which R is hydroxyethyl may be prepared by treating the correspondingl-substituted compound with ethylene oxide. The described reactions maybe illustrated as follows:

X1 X l0 CH2 (CHz)m N-CHz-CH2OH S in which X X A and A are as describedand do not partake in or interfere with the reactions.

The novel compounds of the present invention may be used asintermediates in the preparation of more complex chemical andpharmaceutical compounds, and because of their antiserotonin activityare valuable pharmacological tools. In addition, they are useful aspharmaceuticalagents, per se, because of their antipsychotic properties,especially their ability to control antisocial aggressive behavior whenadministered to animals. For example, the compounds 1 (3,4dimethoxybenzyl)- 1 ,2,3,4-tetrahydrobenzothieno [2,3-C] pyridinehydrochloride, 2 ,8 diethylaminopropionyl 1 phenyl-1,2,3,4-tetrahydrobenzothieno[2,3-C]pyridine hydrochloride, 1- (p-chloroph'enyl)1,2,3,4 tetrahydrobenzothieno- [2,3-C]pyridine and 2 ,3 hydroxyethyl 1-'methyl- 1',2 ,3,4 tetrahydrobenzothieno[2,3 C] pyridine hydrochloridehave shown at a safe and eifective dose of approximately mgL/kg.intraperitoneally an ability to decrease or inhibit the antisocialbehavioral characteristics such as aggressiveness',-;viciousness and.persistence for fighting, induced by isolation in mice. The compoundswere found to have LD s in mice in excess of 50 mgT/kgf''intraperit'oneally in behavioral studies conducted accordance withprocedures outlined by Irwin in Animal and Clinical PharmacologicTechniques in Drug Evaluation, J. H. Nodine and P. E. Siegler, Ed., YearBook Publishers, Inc. 1964, pp. 36-54. The following compounds werefound to" lower bloodpressure when administered in 3:0 and 10.0mgJkgi-iirtravenous doses'toi-the 'vag'otomized', anesthesi'zed dogpreparation, which is-a standardanimal preparation forte's ting'forantihyp'e'rtensive activity. 1

1-(3,4-dirnethoxybenzyl)-1,2,3,4tetrahydrobenzothieno- [2,3-C]pyridinehydrochloride,Z-B-diethylaminopropionyl-l-phenyl-l,2;3,4-tetrahydrobenzothieno[2,3-C]pyridinehydrochloride, andZ-fl-hydroxyethyl-l-methyl-1,2,3,4-tetrahydrobenzothieno [2,3-C]pyridine hydrochloride 4 The novel compounds in which R is"BAm are alsouseful as they form salts with penicillins which can be I used to aid intheisolation and purification of the antibiotics.

Acid addition salts of the compounds of the present invention may beconveniently prepared by contacting the compounds which are capable offorming such salts with a suitable acid such as formic acid,'ci tricacid, maleic acid, sulfuric acid, hydrochloric acid, succinic acid,tartaric acid, benzoic acid or fumaric acid.

Quaternary ammonium salts may be formed by contacting the salt formingcompounds with a suitable alkylating agent such as dimethyl sulfate oran alkyl halide such as methyl chloride, methyl iodide or ethyl bromide.

When intended for use as pharmaceuticals, the compounds are preferablycombined with a major amount of one or more suitable pharmaceuticaldiluents and formed into unit dosage forms. Such dosage forms providesuitable means for oral and parenteral administration.

The pharmaceutical diluents which may be employed may be either liquidor. solid, butthepreferred liquid carrier is water. In theevent the,compound is not soluble in Water a pharmaceutically acceptableorganic.solvent such as propylene glycol may be employed.

Solid pharmaceutical diluents such as starch, sugar and talc can beutilized to form powders which can in turn be used as such or may betableted or encapsulated. In addition to the forementioned material,- awide variety of conventional pharmaceutical lubricants, disintegrat ingagents, flavoring agents 'and the like, may also be employed.

The unit dosage forms may contain a concentration" of 0.1% to 10% ormore by weightof one or'more of ,3- -thianaph'thenyl ethylamine To asuspension of 21 g. (0.55 mole) of lithium'aluminum hydride in 450 ml.of anhydrous ether is added a solution of 31.7 g. (0.18 mole) of3-cyanomethylthianaphthene in 350ml; of anhydrous ether in 45rninutes.The mixture is stirred at room temperature for 3' hours after whichthe'complex-is decomposed bythe dropwise' addition of 80 ml. of water.The solids'are removed by filtration and washed-with "ether. Thefiltrate is dried and concentrated in vacuo to yield a brown oil whichis fractioned to yield B-(3-thianaphthenyl)ethylamine' in the form of aclear liquid, B.P'. 109l10/0.3 'mm.

Ana'lysis.-Calcd. forC H NS (percent): C, 67.75;

H, 6.2 6; N, 7.90. Found (percent): C,'67.49; H, 6.50;

EXAMPLE 2 N-}8-(3-thianaphthenylethyl) acetamide To 5.6 g. (0.03 mole)of 3-(3-thianaphthenyl)ethylamine is added 72 ml. of 20% sodiumhydroxide solution with cooling in 10 minutes. Acetic anhydride (20 ml.)is then added dropwise with cooling within 15 minutes, after which themixture is stirred with cooling for 1 hour and at room temperature for16' hours. The mixture is extracted three times with 100 ml. portions ofether. The extracts are combined and washed three times with 50 ml. ofbrine, dried, and concentrated in vacuo to yield a clear liquid which iscrystallized from benzene/petroleurn-ether to yieldN-/3-(3-thianaphthenylethyl)acetamide in the form of a white crystallinesolid, M.P. 67-68.5.

Analysis.-Calcd. for C H NOS (percent): S, 14.62. Found (percent): S,14.73.

EXAMPLE 3 1-methyl-3,44lihydrothianaphtheno [2,3-C] pyridine A mixtureof 2.4 g. of phosphorus pentoxide, 1.3 g. of N ,8(3-thianaphthenylethyl)acetamide, and 2.4 g. of phosphorus oxychloridein 40 ml. of anhydrous xylene (over sodium) is allowed to reflux undernitrogen for 70 minutes.

The mixture is decomposed with ice and the mixture stirred until a clearaqueous layer is formed. The aqueous layer is separated, washed withbenzene, made basic with concentrated sodium hydroxide solution, andextracted with three 100 ml. portions of benzene. The combined benzeneextracts are dried over anhydrous sodium sulfate and the solventdistilled under diminished pressure to give a solid product. After onerecrystallization from petroleum ether 1methyl-3,4-dihydrothianaphtheno[2,3-C] pyridine, M.P. 73.5 in the formof light yellow needles is obtained.

Analysis.Calcd. for C H NS (percent): S, 15.97. Found (percent): S,15.98.

EXAMPLE 4 l-methyl-1,2,3,4-tetrahydrobenzothieno [2,3-C] pyridinehydrochloride To a dispersion of 1.6 g. (0.042 mole) of lithium aluminumhydride in 250 ml. of ether is added a solution of 2.1 g. (0.01 mole) of1 methyl-3,4-dihydrobenzothieno [2,3-C]pyridine in 50 ml. of ether in 20minutes, after which it is refluxed for hours. The mixture is cooled andthe complex decomposed with the dropwise addition of 15 ml. of water.The solids are removed by filtration and the filtrate dried and madeacidic with ethereal hydrogen chloride. The resulting solids arecollected and recrystallized twice from ethanol to yield1-methyl-1,2,3,4- tetrahydrobenzothieno[2,3-C]pyridine hydrochloride inthe form'of a white crystalline solid, M.P. 255-257.

Analysis.Calcd. for C H ClNS: (percent): C, 60.12; H, 5.88; N, 5.83; S,13.38. Found (percent): C, 60.16; H, 5.79; N, 5.87; S, 13.46.

EXAMPLE 5 1(pchlorophenyl)-1,2,3,4-tetrahydrobenzothieno[2,3-C] pyridineA solution of 3.0 g. (0.017 mole) of fi-(3-thianaphthenyl) ethylamineand 3.1 g. of (0.022 mole) of pchlorobenzaldehyde in ml. of glacialacetic acid is heated on a steam bath for 20 minutes after which it isstirred at room temperature overnight. It is then diluted with 75 ml. ofwater, adjusted to basicity by the addition of potassium carbonate andcooled. The precipitated solids are collected and recrystallized fromisopropanol to yield l-(p-chlorophenyl)-1,2,3,4-tetrahydrobenzothieno[2,3-C]pyridine in the form of a light textured white crystallinesolid,M.P. 57.5-60. 1

14 Analysis.--Calcd. for C 'H CINS (percent): C, 68.12; H, 4.71; S,10.69. Found (percent): C, 68.14; H, 4.49; S, 10.84.

EXAMPLE 6 1-(4'-pyridyl)-1,2,3,4-tetahydrobenzothieno[2,3-C] pyridine Asolution of 3.0 g. (0.017 mole) of B-(3-thianapl1- thenyl) ethylamineand 2.36 g. (0.022 mole) of 4-pyridine-carboxaldehyde in 10 ml. ofglacial acetic acid is heated on a steam bath for 20 minutes after whichit is stirred at room temperature for 5 hours. It is then diluted withml. of water, adjusted to basicity by the addition of sodium carbonateand extracted twice with 50 ml. portions of ether. The extracts arecombined, washed with brine, dried and concentrated to yield an oilwhich is fractioned to yield 1 (4'-pyridyl)-1,2,3,4-tetrahydrobenz0-thieno[2,3-C] pyridine in the form of a clear yellow oil, B.P.167171/0.025 mm.

A{rtalysis.-Calcd. for C H N S (percent): C, 72.14; H, 5.30; N, 10.52;S, 12.04. Found (percent): C, 71.79; H, 5.51;N, 10.33; S, 12.32.

EXAMPLE 7 l-phenyl-1,2,3,4-tetrahydrobenzothieno [2,3-C] pyridine To asolution of 6.1 g. (0.03 mole) of fl-(3-thianaphthenyl)ethylamine in 30ml. of glacial acetic acid is added 4.9 ml. (5.2 g., 0.05 mole) ofbenzaldehyde. It is heated on a steam bath for 20 minutes and stirred atroom temperature for 16 hours. It is then diluted with ml. of water,neutralized with potassium carbonate and extracted twice with 100 ml.portions of ether. The extracts are combined, washed with 50 ml. ofbrine, and concentrated to yield a solid which is recrystallized fromisopropanol to yield 1 phenyl-l,2,3,4-tetrahydrobenzothieno[2,3-C]pyridine in the form of a light-green crystalline solid in two crops,M.P. 58-59".

Analysis.-Calcd. for C H NS (percent): C, 76.96; H, 5.69; N, 5.28; S,12.08. Found (percent): C, 77.11; H, 5.85; N, 5.43; S, 12.26.

EXAMPLE 8Z-B-diethylaminopropionyl-l-phenyl-1,2,3,4-tetrahydrobenzothieno[2,3-C]pyridinehydrochloride To a solution of 4.3 g. (0.024 mole) of 3-(diethylamino)propionic acid hydrochloride in 5 ml. of water is added 0.95 g. (0.024mole) of sodium hydroxide flakes and the mixture is cooled until a clearsolution is obtained. Benzene (100 m1.) is added and the mixtureconcentrated to yield a viscous oil to which 20 ml. of thionyl chlorideis added in 5 minutes. The mixture is stirred at room temperature 1.5hours, heated to 60 and the excess thionyl chloride removed in vacuoafter which two 50- ml. portions of benzene are added and successivelyconcentrated. Benzene (100 ml.) and 3.84 g. (0.038 mole, 5.3 ml.) oftriethylamine are added to the above mixture. The reaction mixture iscooled to 30 and a solution of 5.0 g. (0.019 mole) ofl-phenyl-l,2,3,4-tetrahydrobenzothieno[2,3-C] pyridine in 50 ml. ofbenzene is added in 5 minutes. It is stirred at room temperature 0.5hours, heated to 80 for 20 minutes, cooled to room temperature andfiltered. The filtrate is concentrated to yield a dark residue which isdissolved in 250 ml. of water and 50 m1. of brine, washed with benzene,ether, and finally filtered. The filtrate is made basic with 10% sodiumhydroxide solution and extracted twice with benzene. The combinedextract is treated with activated charcoal and concentrated to yield aviscous oil. Petroleum ether (200 ml.) is added to the residue, refluxedfor /2 hour and decanted. This procedure is repeated and the combinedorganic solution concentrated to yield a gold oil which is dissolved inether and made acidic by the addition of ethereal hydrogen chloride. Thesolid is collected and recrystallized from a solution of benzene andcyclohexane to yield Z-B-diethylaminopropionyl-l-phenyl 1,2,3,4tetrahydrobenzothi- 15 eno[2,3 C]pyridine hydrochloride in the form of alight grey powder, M.P. 188-189.5.

Analysis.-Ca-lcd. for C Jl ClN OiS (percent): C, 67.18; H, 6.82; CI,8.26; N, 6.53. Found (percent): C, 66.97; H, 6.71; 01-, 8.26; N, 6.36.

EXAMPLE 9 2- -diethylaminopropyl-l-phenyl-l,2,3,4-tetrahydrobenzothieno[2.3-] pyridine fumarate To a dispersion of 2.0 g. (0.053 mole) oflithium aluminum hydride in 200 ml. of ether is added a solution of 6.9g. (0.018 mole) of 2-p-diethyl-aminopropionyl-1-phenyl-l,2,3,4-tetrahydrobenzothieno [2,3-C]pyridine in 20 minutes afterwhich it is refluxed for |V2 hours. The compelx is decomposed by theaddition of 15 ml. of water and the solids removed by filtration. Thefiltrate is concentrated and the residual oil ehromatographed throughaluminum oxide (200 g., 3 cm.) using 1.2 liters of varying proportionsof benzene and petroleum ether to yield an oil. it is dissolved in 25ml. of ethanol and a solution of 0.93 g. (0.008 mole) of fum'aric acidin 25 ml. of ethanol added. The solution is diluted with petroleum etherand cooled. The mother liquor is decanted and the semisolid residueCOIVCIBd with ether and again cooled. After the material has completelysolidified, it is collected and recrystallized from ml. of isopropanoland again from ml. of ethanol and diluted with ether to yield 2--diethylaminopropyl 1phenyl-1,2,3,4-tetrahydrobenzothieno[2,3-C]pyridine fumarate in the formof a light grey powder, M.P. 106-109.

Analysis.-Calcd. for 0 11 151 048 (percent): C, 68.00; H, 6.93; N, 5.66.Found (percent): C, 68.12; H, 6.94; N, 5.70.

EXAMPLE 10 Z-B-hydroxyethyl- 1-methyl-1,2, 3,4-tetrahydrobenzothieno [2,3-C] pyridine hydrochloride To a solution of 4.06 g. (0.02 mole) ofl-methyl- 1,2,3,4-tetrahydrobenzothieno[2,3-C] pyridine in 40 ml. ofabsolute alcohol cooled to 0 is added 1.8 g. (0.04 mole) of ethyleneoxide in 20 ml. of cooled absolute alcohol. The reaction mixture isstirred at room temperature for 3 hours and heated to reflux in 2 hours.It is concentrated in vacuo, and the syrup residue dissolved in 300 ml.of anhydrous ether. The insoluble material is removed by filtration. Thefiltrate is adjusted to pH 6 by the slow addition of ethereal hydrogenchloride, and the resulting solid collected and recrystallized twicefrom isopropanol to yieldZ-fl-hydroxyethyl-l-methyl-1,2,3,4-tetrahydrobenzothieno[2,3-C]pyridinehydrochloride in the form of a white powdered solid, M.P. 1 82-1842Analysis.Calcd. for C H CINOS (percent): C, 59.24; H, 6.3'9;N, 4.94; S,11.30. Found (percent): C, 59.04; H, 6.55; N, 4.94; S, 11.01.

EXAMPLE 11 1-(3,4-dimethoxybenzyl)-3,4-dihydrobenzothieno[2,3-C]PY idineTo a solution of 16.7 g. (0.117 mole) of phosphorus pentaoxide and 16.7g. (0.109 mole, 10 ml.) of phosphorus oxychloride in 280 ml. ofanhydrous xylene is added 14.6 g. (0.0412 mole) ofN-(3,4-dimethoxyphenylacetyl) -p-3-thianaphthylethylamine in 2 minutes.The mixture is heated to 120 in 0.5 hour and maintained for 40 minutes.The mixture is cooled to 25 and poured into 400 ml. of ice water. Themixture is then added back to the original reaction flask and stirredwith 10% sodium hydroxide solution (300 ml.) and 200 ml. of benzene at50 for 3 hours. The organic layer is separated, treated with activatedcharcoal, dried, and concentrated to yield 1 (3,4 dimethoxybehzyl) 3,4dihydrobenzothieno- [2,3-ClPYridine as a dark yellow oil whichsolidifies upon cooling.

I 16 EXAMPLE 12.

1-( 3 ,4-dimethoxybenzyl) -1,2,3,4-tetrahydrobenzothieno [2,3-C]pyridinehydrochloride A solution of 6.2 g. (0.018 mole) of1-(3,4-dimethoxybenzyl) 3,4 dihydrobenzthieno[2,3-C]pyridine in ml. ofbenzene is added to a dispersion of 2.8 g. (0.075 mole) of LAH in 200ml. of ether in 10 minutes and refluxed for 3.5 hours. The complex isdecomposed with 15 ml. of water. The solids are removed by filtration;the filtrate concentrated to yield an oil which is dissolved in 250 ml.of ether and filtered through Celite. The filtrate is again concentratedto yield the crude base.

A portion of this material (1.5 g.) is dissolved in 100.

ml. of ether and adjusted to acidity by the addition of etherealhydrogen chloride. The resulting solids are col lected andrecrystallized from 200 ml. of ethanol, concentrated to 75 ml., anddiluted with ether to yield 1-(3,4- dimethoxybenzyl) 1,2,3,4tetrahydrobenzothieno[2,3- C]pyridine hydrochloride as a yellow solid;M.P. 222-- 227".

Analysis.-Calcd. for C H ClNO S (percent): N, 3.73; S, 8.54. Found(percent): N, 3.65; S, 8.22.

EXAMPLE 13 p-(3-thianaphthenyl)propionamide A mixture of 30 g. (0.145mole) of B-thianaphthenepropionic acid and 50 ml. (0.7 mole) of S001, isheated 'y-(3-thianaphthenyl)propylamine hydrochloride To a dispersion of13.4 g. (0.354 mole) of LiAlI-L in 200 ml. of ether is added adispersion of 24.2 g. (0.118 mole) of 3-thianaphthenepropionamide in 800ml. of ether in 0.5 hours. The mixture is refluxed for 16 hours afterwhich 200 ml. of benzene is added and refluxed again for 1.5 hours. Thecomplex is decomposed with 60 ml. of water and the solid removed byfiltration. The filtrate is dried (Na SO and concentrated to yield atheoretical amount of an oil. A 3.0 g. portion of this material isdissolved in ether and acidified with ethereal HCl. The solids arecollected and recrystallized twice from 2- propioual to yield-(3-thianaphthenyl)propylamine hydrochloride as white crystals, M.P.187-189.

Analysis.--Calcd. for C H ClNS (percent): C, 58.00; H, 6.20; N, 6.16.Found (percent): C, 58.27; H, 6.30; N, 6.16.

EXAMPLE 15 N-propionyl-y-(3-thianaphthenyl)propylamine T o a solution of9.1 g. (0.098 mole) of propionyl chloride in ml. of benzene is added asolution of 15 g. (0.0784 mole) of -(3-thianaphthenyl)propylamine and7.75 g. (0.098 mole) of pyridine in 0.5 hour at 10. The

mixture is stirred at 10 for 1 hour, at 25 for 17.5 hours,

and refluxed for 1.5 hours. The mixture is cooled and 100 ml. of wateradded and stirred 5 minutes. The organic layer is separated and washedsuccessively with 100 ml. 10% HCl solution and 50 ml. of brine. It isdried (Na SO and concentrated to yield thetheoretical amount of a yellowoil. A 5.0 g. portion is chromat-- ographed through alumina usingvarying proportions of benzene/petroleum ether and ether/ benzene toyield an oil which crystallized on standing to yield a light yellowsolid, M.P. 5557.5.

17 Analysis.-Calcd. for C H NSO (percent): C, 67.97; H, 6.92; N, 5.66;S, 12.95. Found (percent): C, 68.21; H, 6.92; N, 5.535; S, 13.08.

EXAMPLE l6 1-ethyl-3 ,4-dihydro-H-benzothieno [2,3-C] azepine fumarateethanolate A mixture of g. (0.0404 mole) of N-(propionyl)-3-(B-aminopropyl)thianaphthene, 16.4 g. (1.15 moles) of P 0 and 16.4 g.(1.06 moles) of POCl in 250 ml. of xylene is refluxed for 2 hours. Themixture is cooled and 400 m1. of water added. The mixture is basifiedwith NaOH flakes after which 200 ml. of CHCl is added and stirredminutes. The organic layer is separated, washed with brine, dried (Na SOand concentrated to yield a brown oil which is chromatographed throughalumina using benzene as the eluent to yield a yellow oil whichcrystallized upon standing.

A portion of this material (2.5 g., 0.011 mole) is dissolved in ml. ofethanol and added to a solution of 1.4 g. (0.012 mole) of fumaric acidin ml. of ethanol, filtered and cooled. The solids are collected anddried to yield 1-ethyl-3,4-dihydro-5H-benzothieno[2,3-C]azepine fumarateethanolate as a yellow solid, -M.P. 158-160.

Analysis.-Calcd. for C I-I NSO (percent): C, 61.40; H, 6.40; :N, 3.58;S, 8.19. Found (percent): C, 61.45; H, 6.72; N, 3.60; S, 8.15.

EXAMPLE l7 l-ethyl-1,2,3,4-tetrahydro-5H-benzothieno- [2,3-C1azepinehydrochloride To a dispersion of 2.4 g. (0.63 mole) of LiAlH in 1 00 ml.of tetrahydrofuran is added a solution of 3.6 g. (0.016 mole) of1-ethyl-3,4-dihydro-5H-benzothieno- [2,3-'C]azepine in 100 ml. oftetrahydrofuran in 10 minutes after which it is refluxed for 8 hours.The complex is decomposed with 15 m1. of water and filtered. Thefiltrate is dried and concentrated to yield an oil which waschromatographed through A1 0 using ether as an eluent to yield acrystalline solid which is dissolved in ether and acidified withethereal HCl. The solids are collected and refluxed in 60 ml. ofacetonitrile and cooled. The solids are collected and dried to yield1-ethyl-1,2,3,4-tetrahydro- SH-benzothieno[2,3-C1azepine hydrochlorideas a white powder, M.P. 238-240".

Analysis.-Calcd. for C H ClNS (percent): C, 62.78; H, 6.78; N, 5.24.Found (percent): C, 62.97; H, 7.05; N, 5.04.

I claim:

1. A compound selected from the group consisting of a compound of theformula in which R and R are hydrogen or lower alkyl; and X is hydrogenand X is phenyl halophenyl, loWer-alkoxy benzyl anddi-lower-alkoxy-benzyl, and the pharmaceutically acceptable acidaddition salts thereof.

2. A compound of claim 1 in which A and A are hydrogen.

3. A compound of claim 1 in which R is H and X is phenyl, halophenyl,benzyl or lower al'koxy-substituted benzyl.

4. A compound of claim 1 in which R is BAm and X is phenyl.

5. A compound of claim 1 in which A, A and R are hydrogen and X ischlorophenyl.

6. A compound of claim 1 in which A, A and R are hydrogen and X isdimethoxybenzyl.

7. A compound of claim 1 in which X is phenyl and R is (CH ),,OH inwhich n is 2.

References Cited UNITED STATES PATENTS 6/ 1970 Sub 260294.8

OTHER REFERENCES ALAN L. ROTMAN, Primary Examiner U.S. Cl. X.R.

260-2471, 268 TR, 293.57, 294.7 C, 313.1, 326.5 SA, 330.5; 424--250,263, 267, 274, 275

